Polycythemia vera is one of four recognized myeloproliferative disorders in humans and is thought to be a clonal abnormality of stem cells, manifesting primarily as erythrocytosis (increased red cell mass). Although the molecular mechanisms of aberrant hematopoiesis remain enigmatic, there is distinct evidence for both genetic and environmental influences in disease pathogenesis. The paucity of familial cases and clinical heterogeneity in humans suggest that gene-environment interactions play a significant role in the pathogenesis of the disorder. Environmental factors associated with erythrocytosis range the gamut from dietary and occupational exposure (cobalt), to tobacco smoking, to geographical circumstances (high altitude). The mouse Polycythemia mutation, Pcm, was generated by radiation mutagenesis, and results in a transient erythrocytosis in the heterozygous state. Our preliminary genetic mapping studies are consistent with a single locus causing the Pcm phenotype. We hypothesize that this phenotype associated with Pcm is due to haploinsufficiency for a hematopoietic regulator, and that Pcm mice will provide us with a valuable animal model system for polycythemia vera. The principle goals of this project are to fully characterize Pcm at a genetic and cellular level, and thereby gain insight into the contributions of genetic and environmental factors in the pathogenesis of hematopoietic disorders. The ability to study this mutation on a well-defined, uniform genetic background will allow us to systematically elucidate potential gene-environment interactions. We will specifically test the hypothesis that the discrete and transient erythrocytosis observed in Pcm can be exacerbated by environmental factors, such as cobalt exposure. This would be consistent with the interpretation that the single-locus Pcm mutation predisposes the organism to environmental insult that would subsequently unmask a more severe manifestation of disease. Therefore, the aims of my research include phenotypic characterization of Pcm, genetic mapping of the locus, and subsequent positional cloning of Pcm.